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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The use of cell lines as biologic "minipumps" to chronically deliver antinociceptive molecules such as the peptide galanin near the pain processing centers of the spinal cord after nerve injury is a newly developing technology for the treatment of neuropathic pain. The neuronal rat cell line, RN33B, derived from E13 brainstem raphe and immortalized with the SV40 temperature-sensitive allele of large T antigen (tsTag), was transfected with rat preprogalanin (GAL) cDNA and the galanin-synthesizing and -secreting cell line, 33GAL.19, was isolated [1]. The 33GAL.19 cells transfected with the GAL gene expressed immunoreactivity (ir) for the GAL protein and synthesized low levels of GAL-ir at permissive temperature (33 degrees C), when the cells were proliferating, and increased GAL-ir during terminal differentiation at non-permissive temperature (39 degrees C) in vitro. A control cell line, 33V.1, RN33B cells transfected with the pCEP4 vector alone and similarly isolated by subcloning, contained no detectible GAL-ir at either temperature in vitro. These cell lines were used as grafts in a model of chronic neuropathic pain induced by unilateral chronic constriction injury (CCI) of the sciatic nerve. Pain-related behaviors, including cold and tactile allodynia and thermal and mechanical hyperalgesia, were evaluated in the affected hindpaw after CCI and transplants. The 33GAL.19 and 33V.1 cells transplanted in the lumbar subarachnoid space near the spinal cord one week after CCI, survived at least seven weeks on the pial surface around the spinal cord and only the 33GAL.19 cells expressed GAL-ir in vivo after transplant. Furthermore, the tactile and cold allodynia and tactile and thermal hyperalgesia induced by CCI was significantly reduced or eliminated during the two to seven week period after grafts of 33GAL.19 cells. The maximal effect on chronic pain behaviors with the GAL grafts occurred one to three weeks after transplantation. Transplants of 33V.1 control cells had no effect on the allodynia and hyperalgesia induced by CCI. These data suggest that a chronically applied, low local dose of galanin supplied by transplanted cells near the lumbar spinal dorsal horn was able to reverse the development of chronic neuropathic pain following CCI. The use of transplants of genetically modified neural cell lines that are able to deliver antinociceptive molecules, such as galanin, offers a safe and novel approach to pain management.
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PMID:Lumbar transplant of neurons genetically modified to secrete galanin reverse pain-like behaviors after partial sciatic nerve injury. 1064 92

Galanin has been implicated in various physiological functions including memory, feeding and pain perception. Using rat cerebral cortical slices and synaptosome preparations incubated with [(3)H]choline in Kreb's-Ringer solution, galanin was shown to inhibit both spontaneous and K(+)-stimulated [(3)H]ACh release in a concentration-related manner [EC(50)= 35 nM]. The galanin-mediated inhibition on spontaneous and K(+)-stimulated [(3)H]ACh release was respectively regulated by pertussis toxin-sensitive G(alphai3)and G(alphai1). These suggest that galanin is a negative modulator of cortical cholinergic function and most probably acting on presynaptic cholinergic terminals. Although galantide blocked the galanin-mediated inhibitory effect on [(3)H]ACh release, it mimicked galanin in blocking K(+)-stimulated [(3)H]ACh release, indicating that galantide may have a more complicated pharmacology than being a galanin receptor antagonist. In addition, we demonstrate that galanin and beta-amyloid peptide(1-42)synergistically attenuated K(+)-evoked [(3)H]ACh release from synaptosomes prepared from rat cerebral cortex. Since galanin is increased in Alzheimer's disease brain, our results suggest that galanin may be involved in cholinergic dysfunctions that occur in Alzheimer's disease.
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PMID:Galanin inhibits acetylcholine release from rat cerebral cortex via a pertussis toxin-sensitive G(i)protein. 1065 92

The neuropeptide galanin has been identified as a potential neurotransmitter/neuromodulator within the central nervous system. In the present study, the role of endogenous galanin in nociceptive processing in the nervous system has been analysed by using mice carrying a targeted mutation in the galanin gene. Supporting this, the effect of chronic administration of exogenous galanin on nociceptive sensory inputs has been assayed in adult rats. In the absence of peripheral nerve injury, the sensitivity to threshold noxious stimuli is significantly higher in galanin mutant mice than wild-type controls. Following peripheral nerve injury, in conditions under which endogenous galanin levels are elevated, spontaneous and evoked neuropathic pain behaviours are compromised in mutant mice. Conversely, chronic intrathecal delivery of exogenous galanin to nerve-intact adult rats is associated with persistent behavioural hypersensitivity, a significant increase in c-fos expression and an increase in PKCgamma immunoreactivity within the spinal cord dorsal horn. The present results demonstrate that a relationship exists between the degree of nerve injury-induced galanin expression and the degree of behavioural hypersensitivity, and show that galanin may play a role in nociceptive processing in the spinal cord, with interrelated inhibitory and excitatory effects.
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PMID:Galanin knockout mice reveal nociceptive deficits following peripheral nerve injury. 1076 8

The aim of this investigation was to determine whether murine models of inflammatory, neuropathic and cancer pain are each characterized by a unique set of neurochemical changes in the spinal cord and sensory neurons. All models were generated in C3H/HeJ mice and hyperalgesia and allodynia behaviorally characterized. A variety of neurochemical markers that have been implicated in the generation and maintenance of chronic pain were then examined in spinal cord and primary afferent neurons.Three days after injection of complete Freund's adjuvant into the hindpaw (a model of persistent inflammatory pain) increases in substance P, calcitonin gene-related peptide, protein kinase C gamma, and substance P receptor were observed in the spinal cord. Following sciatic nerve transection or L5 spinal nerve ligation (a model of persistent neuropathic pain) significant decreases in substance P and calcitonin gene-related peptide and increases in galanin and neuropeptide Y were observed in both primary afferent neurons and the spinal cord. In contrast, in a model of cancer pain induced by injection of osteolytic sarcoma cells into the femur, there were no detectable changes in any of these markers in either primary afferent neurons or the spinal cord. However, in this cancer-pain model, changes including massive astrocyte hypertrophy without neuronal loss, increase in the neuronal expression of c-Fos, and increase in the number of dynorphin-immunoreactive neurons were observed in the spinal cord, ipsilateral to the limb with cancer. These results indicate that a unique set of neurochemical changes occur with inflammatory, neuropathic and cancer pain in C3H/HeJ mice and further suggest that cancer induces a unique persistent pain state. Determining whether these neurochemical changes are involved in the generation and maintenance of each type of persistent pain may provide insight into the mechanisms that underlie each of these pain states.
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PMID:Murine models of inflammatory, neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons. 1086 52

Mechanisms involved in transition from acute to chronic pain are still not well understood and our means to therapeutically influence this transition are limited. Moreover, very little is known about long-lasting consequences of prolonged exposure to painful stimuli with regard to phenotypic changes and pain experience. In this study we have analyzed long term behavioral and neurochemical effects of intradermal tail injection of heat-killed mycobacterium butyricum suspended in complete Freund's adjuvant. Calcitonin gene-related peptide (CGRP) and galanin mRNA levels were investigated in dorsal root ganglia of polyarthritic rats during the acute (21-) and the remission stage (79 days postinjection), and opioid peptide mRNAs and receptors were studied in the spinal cord. Most of the increases in peptide mRNA levels observed during the acute stage of arthritis were still present in the remission stages. Thus, CGRP and galanin mRNAs in DRGs, and opioid peptide mRNAs and opioid receptors in the spinal cord were still strongly up-regulated, when animals do not exhibit spontaneous pain behavior and inflammation. Hot-plate test in the presence of naloxone, performed in the remission stage, indicated that opiates participate in pain threshold regulation after prolonged painful condition. Finally, X-ray examination revealed a complete destruction of joint structure, thus suggesting a parallel lesion of peripheral nerve endings. These results suggest that in the remission stage of chronic joint inflammation several types of mechanisms are activated aiming at counteracting both inflammatory and neuropathic pain. Thus, opioid systems in the dorsal horn as well as galanin in DRG neurons are upregulated, both alternating pain.
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PMID:Long-lasting regulation of galanin, opioid, and other peptides in dorsal root ganglia and spinal cord during experimental polyarthritis. 1091 72

Visceral disorders are always accompanied by pain and/or a sense of ill-being that entails people to isolate themselves both physically and socially. By analogy with what happens in human beings, we have transferred to the rat the question of whether a protective, dark and quiet environment would influence the brain activities induced by visceral chemically-induced (cyclophosphamide [CP], 100 mg/kg/ip) adverse conditions of life. CP is an antitumoral drug that induces severe side effects (cystitis, headache, nausea, photophobia, phonophobia) and produces a strong state of ill-being in human beings. Brain activities were quantified using the expression of the Fos protein, a molecular marker of neuronal activity. The results compare data from groups of paired animals having been offered a shelter or not. Data were collected 4 h after the injection of CP, i. e., when cystitis was fully developed. Sheltered and unsheltered groups did not differ in bladder pathology. Intentional sheltering was shown to attenuate the expression of the CP-related Fos-Li activity within the locus coeruleus (LC) without affecting that of the structures known preferentially to process nociceptive inputs of bladder origin (dorsal vagal complex, ventrocaudal bulbar reticular formation, nucleus centralis of amygdala, dorsolateral portion of bed nucleus of stria terminalis). The LC levels of tyrosine hydroxylase and galanin neuronal contents were not affected. The LC belongs to the emotional activation system and can respond to a wide range of somatosensory and viscerosensory stimuli. Our hypothesis is that the LC would be processing the nervous activities that accompany the sense of ill-being coming from adverse conditions of life, including visceral disorders, and that voluntary isolation, by reducing its activity, would enable animals to minimize their level of distress.
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PMID:Environmental influences on viscero(noci)ceptive brain activities: the effects of sheltering. 1097 98

The mechanism of spinal tolerance to the analgesic effects of opiates is unclear at present. We have reported previously that calcitonin gene-related peptide-like immunoreactivity was significantly increased in primary afferents of the spinal dorsal horn during the development of morphine tolerance, suggesting that changes in the level of pain-related neuropeptides in dorsal root ganglion neurons may be involved [Menard D. P. et al. (1996) J. Neurosci. 16, 2342-2351]. In this study, we investigated if in vitro treatment with morphine can mimic the in vivo findings and induce increases in calcitonin gene-related peptide-like immunostaining in cultured dorsal root ganglion neurons from young (three-month-old) and middle-aged (10-month-old) adult rats. Following a repetitive exposure to morphine sulfate (1, 5, 10 microM) for six days, the number of calcitonin gene-related peptide- and substance P-immunoreactive neurons in cultured dorsal root ganglia from three- and 10-month-old rats was significantly increased. A lower concentration (0.5 microM) of morphine induced these increases only in dorsal root ganglion neurons from middle-aged rats. Morphine treatment was also found to increase the number of calcitonin gene-related peptide-immunoreactive neurons possessing multiple, long branches (i.e. with at least one branch >0.5mm). This apparent increase in the number of calcitonin gene-related peptide- and substance P-immunoreactive neurons observed following morphine treatment was blocked by naloxone, an opiate antagonist, indicating the involvement of genuine opioid receptors. No significant change in the number of neuropeptide Y- or galanin-immunoreactive neurons in cultured dorsal root ganglia was detected following any of these treatments. These data suggest that repeated exposure to morphine rather selectively increases calcitonin gene-related peptide- and substance P-like immunoreactivity in cultured dorsal root ganglion neurons. Moreover, the sensitivity to morphine-induced changes is greater in cultured dorsal root ganglion neurons from 10- compared to three-month-old rats. Hence, cultured dorsal root ganglion neurons can provide a model to investigate the cellular and molecular mechanisms underlying alterations in neuropeptide levels following repeated exposure to opiates and their relevance to the development of opioid tolerance.
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PMID:Morphine treatment induced calcitonin gene-related peptide and substance P increases in cultured dorsal root ganglion neurons. 1102 44

This short review summarizes the effect of various stressful stimuli on the expression of neuropeptides which co-localize in corticotrophin releasing hormone (CRH)-synthesizing neurons in the hypothalamic paraventricular nucleus, as well as in oxytocin and vasopressin neurons in the supraoptic nucleus. Stress-induced changes failed to act on CRH neurons in the central amygdaloid nucleus but formalin-evoked pain enhanced galanin mRNA expression in the medial subdivision of this nucleus. Changes in the expression of enkephalin, galanin, dynorphin and cholecystokinin mRNA in response to restraint and formalin-induced pain are documented in hypothalamic and amygdaloid nuclei by in situ hybridization histochemical technique.
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PMID:Stress-induced expression of co-localized neuropeptides in hypothalamic and amygdaloid neurons. 1103 23

Galanin is a 29-amino acid peptide with a suggested role in nociception. The effect of galanin on wide-dynamic range neuron discharge frequency in rats with nerve ligation, used as a model of neurogenic pain, was investigated by extracellular recording methods. Seven to 14 days after sciatic nerve ligation, 0.1, 0.5 or 1 nmol of galanin was administered directly on the dorsal surface of the L3-L5 spinal cord of rats with sciatic nerve ligation. It was found that galanin inhibited the activity of wide-dynamic range neurons dose-dependently, an effect was more pronounced in sciatic nerve ligated rats than intact rats. Furthermore, when 1 nmol of galantide, the galanin antagonist, was administered on the dorsal surface of the L3-L5 spinal cord, the wide-dynamic range neuron discharge frequency increased significantly. The results suggest that galanin plays an important role in the modulation of presumed nociception in mononeuropathy.
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PMID:Effects of galanin on wide-dynamic range neuron activity in the spinal dorsal horn of rats with sciatic nerve ligation. 1106 28

There is currently some debate over a possible role of galanin in pain processing. It was recently reported that the levels of galanin in dorsal root ganglia (DRGs) seem related to development of allodynia after unilateral sciatic nerve constriction injury. In our present study, we aimed at characterizing the effect of exogenous and endogenous galanin on pain behavior in allodynic and non-allodynic rats in which the levels of galanin in DRG neurons are low and high, respectively [28]. The results show that in allodynic rats, the mechanical threshold increases dose-dependently after intrathecal (i.t.) injection of galanin, while no significant changes were observed in groups treated with the putative galanin antagonist M35 or saline. In non-allodynic rats i.t. injection of M35 induced a significant mechanical allodynic state, which did not occur after injection of galanin, bradykinin, the bradykinin fragment(2-9) or saline. The results suggest that in the present experimental paradigm exogenous galanin has an anti-allodynic effect in the allodynic rats, and that endogenous galanin has a tonic inhibitory effect in the non-allodynic group.
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PMID:Effect of intrathecal galanin and its putative antagonist M35 on pain behavior in a neuropathic pain model. 1111 88


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